Cardiovascular disease is a major public health problem and has been the leading cause of death in the United States for decades. A significant fraction of the disease is the result of atherosclerosis and heart disease. The high fat diet consumed in the Western world is a direct cause of elevated LDL-cholesterol and triglyceride levels in blood which result in the formation of atherosclerotic plaques in the vasculature. Current treatment relies mainly on the reduction of plasma LDL- cholesterol by administering pharmaceuticals that either reduce cholesterol biosynthesis or accelerate cholesterol disposal and requires life-long medications that may have long-term side effects. Hyperlipidemias are polygenic disorders that strongly predispose individuals to the development of atherosclerosis. It is well established in animal studies that the pathologic phenotypes can be prevented or improved by enhanced expression of the LDL-receptor, apolipoprotein A1, cholesterol-7a-hydroxylase and lipoprotein lipase genes. With the advent in technologies for gene transfer into animals that result in their constitutive expression in vivo, the therapeutic genes for atherosclerosis can be introduced somatically into the proper organs for expression that may provide a long-term cure for the disease. As the natural organs for biosynthesis of these genes are the liver and the muscle, and technologies for somatic gene delivery into these organs are already mastered in various laboratories at Baylor College of Medicine, the current program project proposal will focus on the refinement of existing technologies as well as the development of novel vector systems for efficient delivery and enhanced expression of the plasma lipid modulating genes in the liver and the muscle. The initial experimental animal model system will be the Watanabe hereditary hyperlipidemic rabbits and other genetic animal models created by either transgenic introduction of atherosclerotic genes or inactivation of protective genes by targeted recombination in embryonic stem cells. Atherosclerotic animals induced by high fat diet will also be used to test the hypothesis that these plasma lipid-modulating genes are therapeutic for atherosclerosis caused by a wide spectrum of genetic factors. Phenotype correction of plasma lipid profiles and subsequent prevention of atherosclerogenic plaque formation in the vasculature of the genetic and dietary animal model systems will form the scientific basis for the future correction of atherosclerosis and coronary heart disease in man by somatic gene therapy.